Steroid-3-enol-acylates



United States Patent Ofiice This invention relates to steroids. More particularly, it is directed to compounds of the folowing Formula H:

A) n ol wherein:

R is a member of the group consisting of H, CH F and Cl;

R is a member of the group consisting of H and acyl;

R is a lower aliphatic carboxylic acid radical; and

Z is a member of the group consisting of (I-L'H), (H,CH

and =OH The subject matter of the present invention, the steroid- 3-enolacylates of the above Formula II can be prepared by converting a 3-keto-4,6-diene steroid of Formula I:

by treatment with a lower aliphatic enol-acetylating agent, into the corresponding steroid-S-enol-acylate.

It has now been found that the oral action of steroid- 3-enol-acylates of Formula 11 obtained in accordance with the invention is substantially greater than that of the basic steroids of Formula I. From U.S. Patent 2,889,342, there are known steroid-3-enol-acylates which have been prepared from 3-keto-4-ene-steroids which are saturated in 6, 7-position. As has been proven in the Olauberg test, the triply unsaturated stenoid-3 enol-acylates obtained in accordance with the invent-ion have a considerably stronger progestational eifect upon oral adminis-tna tion than the doubly unsaturated steroid-3-enol-acylates described in US. Patent 2,889,342. Thus for 16-methylene-2,4,6-pregnat1iene-20-one-3,17u-diol diacetate, there was found 340% times the efiect of progesterone. The

corresponding 16-methylene-3,S-pregnadiene 20 one Ratented Dec. 3, 1963 3,17a-di0l-d'iacetate was on the other hand only 425 times more effective than progesterone.

The enol-acylation is carried out by the customary methods. It is advantageous for instance to use a mixture of \a lower aliphatic carbonyl chloride and a lower aliphatic carboxylic anhydride as well as possibly in the presence of an organic base such as pyridine. The enclacylation can also be carried out with the use of a mixture of the corresponding oarboxylic anhydride with an organic base such as pyridine. In these enol-acylations, it is not necessary to add a special solvent, since the initial steroids dissolve in the mixtures used as enol-acylating agent. The reaction temperatures are between room temperature and the boiling point of the mixture of the lower aliphatic acid halides and anhydrides used as enol-acylating agent. The reaction times vary between a few hours and two days, depending on the reaction temperatures applied.

The enol-acylation in accordance with the invention can also be carried out with the use of isopropenyl acetate which is customarily used as enol-acetylating agent. In this case, benzene or any other aromatic hydrocarbon such as toluene or xylene is used as solvent. It is furthermore advisable in this reaction to add an acid catalyst, for instance, small amounts of p-toluene sulfonic acid, to the reaction mixture:

The esterifying moiety of R may be the acyl radical of one of the customary esterifying acids used in the steroid art to provide pharmaceutically acceptable esters, as for example, acetic acid and the higher homologues thereof having up to 10 carbon atoms. Thus, the Hot-esters include the following: the formate, the acetate, the propionatc, the bntyr ate, the isobutyrate, the valeriate, the oapronate, the enanthate, the caprylate etc.

R is a lower aliphatic acyl radical having up to 5 carbon atoms. Thus, the present invention includes the 3-en-olacy1ates of the following acids: acetic acid, propionic acid, butyric acid, valeric acid, methyl butyric acid and trimet'nyl acetic acid.

As starting material, there can be used, for instance, the following compounds: 4,6-pregnadiene-3,2O-dione-1711-01 16-methylene-4,6-pregnadiene-3,20-dione-17a-ol 1 6-rnethy1ene-6-methyl-4,6-pregnadiene-3,20-

dione-17a-ol 16-methylene-6-fluoro-4,6-pregnadiene-3,20-

di01'l6-l7u-Ol 16-methylene-6-chloro-4,6-pregnadiene-3,20-

dione-17a-o1 6-metl1yl-4,o-pregnadiene-3,20-dione-1706-01 6-chloro-4,6-pregnadiene-3,20-dione-1711-01 6-fiuoro-4,6-pregnadiene-3,20-dione-17a-ol As starting material, the 17a-acy1ates, particularly the 1711-3CBt21t6S, of the above compounds also enter into consideration.

A hydroxyl group in t-POSitlOI1 in the starting material can be co-esterified in the enol-acylation.

By the foregoing method, there are obtained, for instance, the following steroid-3-enol acylates:

2,4, 6-pre gnatrien e-20-one-3 17a-diol-diacetate 16-methylene-2,4,6-pregnatriene-20-one-3,17a-

diol-diacetate 16-methylene-6-methyl-2,4,6-pregnatriene-20-one- 3,17a-d-iol-diacetate 16-methylene-6-fiuoro-2,4,6-pregnatriene-2l)-one- 3,17a-diol-diacetats 16-methy1ene-6-chloro-2,4,6-pregnatriene-20-one- 3,17a-diol-diacetabe 6-methyl-2,4,6-pregnatriene-20-one-3,17rx-diol-diacetate 6-ch1oro-2,4,6-pregnatIiene-20-one-3,l7a-diol-diacetate 6-fiuoro 2,4,6-pregnatriene-ZO-one-3, 17a-diol-diacetate The new steroid-3-enolacylates are particularly suitable for oral administration. They can be worked into ills, tablets, dragees, solutions or emulsions for oral application by the customary methods of preparation.

The therapeutic effect of the new compounds is substantially higher than that of the basic 3-keto-4,6-dienesteroids. Thus for instance in the Clauberg test on rabbits, 16 methylene-2,4,6-pnegnatriene-20-0ne-3,17a-dioldiacetate upon oral application exhibits 3400 times the action of progesterone, while 16-methylene-4,6-pregnadiene-3,20-dione-17u-ol-acetate has only 460 times the action of progresterone. Similarly, in this test 6-ch-lor0- 4,6-pregnadiene-3,ZO-dione-17a-0l-acetate is 4500 times more effective than progesterone while 6-chloro-2,4,6- pregnatriene-ZO-one-Ii,17a-diol-diacetate is 5700 times more effective. The best preparations available on the market, namely nor-ethynyl-testosterone and 6ct-metl1yl- 17a-acetoxy-progesterone have on the other hand only 600 and 1500 times the effect of progesterone respecti-vely.

In clinical experiments, the new compounds are administered as tablets of 1 and 2 mg, a dose of one tablet twice a day being on the average sufficient.

The invention thus constitutes a substantial advance in the art of providing orally effective progestagenics.

The following are examples in accordance With this invention:

Example 1 1 gram of 4,6-pregnadiene-3,20-dione-17a-ol-acetate is dissolved together with 0.1 gram of p-toluene sulfonic acid in 40 ml. of benzene. 20 ml. of the solution are distilled off and ml. of i opropenyl acetate added. Thereupon the reaction mixture is heated under reflux in a iitrogen atmosphere for 4 hours. The solution is then cooled, the p-toluene sulfonic acid neutralized with a small amount of anhydrous sodium acetate, and the reaction mixture concentrated under reduced pressure. The residue is extracted in ether, and the ethereal solution s aken with dilute sodium bicarbonate solution, dried with sodium sulfate and concentrated. From methanol there crystallizes 2,4,6-pregnatriene--one- 3,17a-diol-diacetate. MP. 228-229 C.; (M -75 (dioxane) k 300 111,11.

Eltm. 342

Example 2 1 gram of 6-fluoro-4,6-pregnadiene3,20-dion;-170mlacetate is heated in 16 ml. of acetic anhydride together with 6.4 ml. of acetyl chloride and 0.64 ml. of pyridine for 3 hours at 100 C. Thereupon the reaction mixture is concentrated in vacuum and the residue recrystallized from methanol. 6 finoro 2,4,6 pregnatriene-ZO-one- 3,17a-diol-acetate is obtained.

Example 3 In a manner similar to Example 1, 16-methylene-2,4,6- pregnatriene-ZO-one-3,17u-diol-diacetate is prepared from 16 methylene-4,6-pregnadiene-3,2O-dione4l7zt-ol-acetate. Ml. 170-172 C.; '(ot) 1S7.5; A 300 m lli. 335

Example 4 In a manner similar to Example 1, 6-methyl-2,4,6- pregnatriene-20-one-3,17a-diol-diacetate is prepared from 6-methyl- 4,6-pregnadiene-3,20-dione-17a-ol-acetate.

Example 5 In a manner similar to Example 1, 16-methylene-6- methyl 2,4,6 pregnatriene 20 one 3,17u diol-diacetate is prepared from 16-methylene-6-methyl-4,6- pregnadiene-3,20-dione-17a-ol-acetate.

Example 6 In a manner similar to Example 2, 6-clrloro-2,4,6-

4 pregnatriene-ZO-one-El,17a-di0l-diacetate is prepared from 6 chloro 4,6 pregnadiene 3,20 dione 170a olao'etate. Melting point 141142 C., A 301 my.

E52,, 308 (u) -47 (dioxane).

Example 7 in a manner similar to Example 2, 16 methylene 6- fluoro 2,4,6 pregnatriene 20 one 3,17a diol diacetate is prepared from 16 methylene 6 fiuoro 4,.6- pregnadiene 3,20 dione 17m ol acetate.

Example 8 in a manner similar to Example 2, 16 methylene 6-- chloro 2,4,6 pregnatriene 20 one 3,17oc diol diacetate is prepared from 16 methylene 6 chloro 4,6- prcgnadiene 3,20 dione 17a ol acetate.

Example 9 1 gram of 6 chloro 4,6 pregnadiene 3,20 dione- 170; ol acetate is heated for 3 /2 hours at C. with 15 ml of butyric anhydride, 7 ml of butyrochloride and 0.7 ml of pyridine. The reaction mixture is concentrated in vacuum, and 6 chloro 2,4,6 pregnatriene 20 one- 3 butyrate 17a acetate recrystallized from methanol. Melting point: 157 to 159 C.

The starting materials employed in preparing the compounds hereinafter ciaimed are described in the following patents and scientific literature, to wit:

4,6 pregnadiene 3,20 dione 17a 01 or the corresponding l7-acetate, for claim 2, US. Patent 2,739,974;

16 methylene 3,20 dione 171x 01 or the corresponding l7-acetate, for claim 3, Tetrahedron Letters, No. 16, page 22, 1960;

16 methylene 6 methyl 4,6 pregnadiene 20 one- 01 or the corresponding 17-acetate, for claim 4, Belgian Patent 594,445;

6 dehydro 6 methyl 17oz acetoxyprogesterone, for

claim 7, JACS, vol. 81, page 3485, 1959;

6 dehydro 6 chloro 171x acetoxyprogesterone, for

claims 8 and 10, JACS, v01. 81, page 3485, 1959;

6 dehydro 6 fiuoro 17a acetoxyprogesterone, for

claims 9 and 11, JACS, vol. 81, page 3485, 1959.

It will be understood that the foregoing description of the invention and the examples set forth are merely illustrative of the principles thereof. Accordingly, the appended claims are to be construed as defining the invention within the spirit and scope thereof.

We claim:

1. 2,4,6 pregnatriene 20 one 3,17a diol diacetate.

2. 16 methylene 2,4,6 pregnatriene 20 one 3, 17oz diol diacetate.

3. 16 methylene 6 methyl 2,4,6 pregnatriene- 20 one 3,1'7oc diol diacetate.

4. 6 methyl 2,4,6 pregnatriene 20 one 3,17ocdiol diacetate.

5. 6 chloro 2,4,6 pregnatriene 20 one 3,1170:- diol diacetate.

6. 6 fiuoro 2,4,6 pregnatriene Z0 one 3,170:- diol diacetate.

7. 6 chloro 2,4,6 pregnatriene 20 one-3-butyrate 17oz acetate.

8. 6 fluoro 2,4,6 pregnatriene 20 one 3 butyrate 17a acetate.

Reierences Cited in the file of this patent UNITED STATES PATENTS 2,926,163 Dauben et a1 Feb. 23, 1960 

1. 2,4,6-PREGNATRIENE-20-ONE-3,17A-DIOL-DIACETATE. 